Cardiovascular disease and stroke remain major public health issues with a disproportionate impact on minority populations and less is known about Hispanics. While our knowledge of vascular risk factors has improved, little is known regarding genetic influences. Evaluation of quantitative cardiovascular precursor phenotypes will facilitate gene discovery and family-based studies provide unique advantages in identifying genetic variants, especially rare variants, associated with these traits. The goal of the Family Study of Carotid Atherosclerosis and Stroke Risk is to identify genetic determinants of specific cardiovascular and stroke risk phenotypes which are precursors to cardiovascular disease and stroke. The family study database consists of 1390 subjects from 100 high-cardiovascular risk Dominican families with systematic evaluations of phenotypes (carotid ultrasound and echocardiography), extensive data collection of traditional and behavioral risk factors including diet, blood and DNA stored, a microsatellite genome wide scan at CIDR, and fine mapping results on various QTLs. We propose to further characterize variants (both common and rare) and genes that contribute to inter-individual variations in carotid intima media thickness, carotid plaque, left ventricular mass, and left atrial diameter by utilizing our extensive Dominican Family Study database. Using next generation sequencing technology, we will pursue peak-wide exome sequencing for our traits and gene-wide sequencing for candidate genes of interest within our selected regions. Regions of interest have been identified in our linkage studies for each of these complex traits. We have prioritized 20 informative families with any trait-specific peak LOD score > 0.4. Importantly, we have the unique ability to combine our Family Study with a validation association study drawn from an independent cohort of Dominicans from our Northern Manhattan Study (NOMAS) who have had identical trait measurements and clinical follow-up. To validate the findings from the peak-wide exome sequencing stage of the families, genes with multiple variants contributing to any of the quantitative traits will be sequenced in unrelated Dominicans in NOMAS. Other validations are planned using the Cohorts for Heart and Aging Research in Genomic Epidemiology and the non-Dominican subjects in NOMAS. Additionally, we propose to re-contact the Dominican subjects in our family study to record any follow-up cardiovascular and stroke events. We will evaluate the association between any selected variants and the risk of stroke, MI or vascular death in the NOMAS cohort. These studies have the potential to identify novel genes underlying complex risk phenotypes in the rapidly growing Hispanic population and help design innovative approaches to modification of risk of cardiovascular disease and stroke. PUBLIC HEALTH RELEVANCE: Cardiovascular disease and stroke are the leading causes of death in the US and have tremendous social and financial consequences. These are complex diseases with strong genetic underpinnings and remain major public health threats especially among the rapidly growing but understudied Hispanic population. The proposed study aims will investigate new genetic determinants using next generation sequencing for subclinical carotid disease and echocardiographic traits among extended Dominican families to help fill gaps in our knowledge of the genetics of cardiovascular disease and stroke risk in minority groups.